Field of the Invention
The present application relates to pharmaceutical quality strontium L-lactate compositions and methods of use. The methods and compositions disclosed herein are particularly useful for providing bioavailable strontium to mammals and treating or preventing bone- and/or cartilage-related disorders.
Description of the Related Art
In the early 1900's, a number of strontium salts of unknown quality and purity were prepared and used medicinally. The “Dispensatory of the United States” (1907) states that strontium lactate, by way of example, was prepared in a step-wise process. [Wood G B, Remington J P, Sadtler S P. The Dispensatory of the United States of America, pp 1661-2. Philadelphia: J B Lippincott Co., 1907.] First, strontium nitrate was washed with ethanol before dissolution in water. Then dilute sulfuric acid was added in an attempt to precipitate barium sulfate and other insoluble metal sulfates and purify the strontium nitrate. After filtration to remove the precipitates, sodium carbonate was added to precipitate the strontium ion as strontium carbonate. After the strontium carbonate was isolated by filtration, it was added to a solution of lactic acid. After reaction was complete, a solution of strontium lactate was obtained. The product of these reactions, strontium lactate, often was not isolated, since strontium lactate is highly soluble in water and alcohols such as methanol and ethanol. Therefore, the aqueous solution containing the salt typically was diluted with glycerol to a known volume, and the diluted solutions were used medicinally. Alternatively, excess water was evaporated and strontium lactate trihydrate or strontium lactate anhydrous was isolated. Historical tests for quality and purity [as disclosed in the “Dispensatory of the United States” (1907) and corresponding “U.S. Pharmacopeias” (through 1955)] consisted of subjective observations about reactivity with acids and bases. Tests for quality and purity such as strontium analysis, HPLC analysis of lactate, HPLC analysis of organic impurities, determination of sterility and absence of endotoxins, were not performed.
More recent preparations of certain strontium salts are described in U.S. patents and their foreign counterparts. U.S. Pat. Nos. 7,589,235, 7,595,342, 8,183,409, 8,541,471, 8,609,616, and 8,623,422 (assigned to Osteologix) disclose two general methods for the preparation of strontium salts—neutralization of an aqueous solution of an organic acid with strontium hydroxide or strontium carbonate (Eq. 1) and anion exchange between a water-soluble strontium salt and a water-soluble salt of an organic acid (Eq. 2).Sr2++2OH−+2CH3CH(OH)COOH→Sr(OC(O)CH(OH)CH5)2  (Eq. 1)Sr2++2CH3CH(OH)COO−→Sr(OC(O)CH(OH)CH3)2  (Eq. 2)The acid-neutralization methods of preparation disclosed in U.S. Pat. No. 7,589,235 and related patents make use of high temperatures (e.g., 80-100° C.), optionally with elevated pressures, to accelerate the formation of strontium salts of organic acids in high yield and purity, where purity is defined as an absence of strontium carbonate contamination in the final product. The methods also disclose use of methanol or ethanol as a co-solvent said to cause precipitation of the strontium salt.
Historical medicinal uses of strontium salts included oral administration as an anthelmintic, antinephritic, diuretic, or tonic. Ingestion of daily doses of 0.3-0.6 grams of strontium lactate were reported to decrease albumin in the urine. Two gram doses twice a day for five days were reported as an effective treatment for worms. In addition, low doses effectively treated arthritis, gout, and involuntary movements (chorea).
Today several strontium salts, including strontium ranelate, strontium chloride, strontium succinate, strontium citrate, and strontium malonate, are reported to be useful for the treatment of bone and cartilage dysfunction, prevention of tooth decay, and prevention or treatment of pain. Two water-insoluble strontium salts, strontium ranelate and strontium succinate, have been approved as drugs for the treatment of osteoporosis in Europe and Australasia. Almost a decade of clinical use of a daily dose of 2 grams of strontium ranelate (680 mg strontium) supports a finding of significantly reduced incidence of fractures in men and women having low bone mass. Similar data gathered over a shorter period of time indicate a daily dose of 1.7 grams of strontium succinate (680 mg strontium) is also highly beneficial in treating osteoporosis. Other recent uses of strontium salts include preventing gastrointestinal side effects of a pharmaceutical product, treatment of rheumatic or arthritic conditions, and prevention or treatment of necrotic bone conditions. In U.S. Patent Application Publication No. US 2008/0090896 Brookler disclosed the use of strontium salts for the treatment of otosclerosis.
Moreover, recent studies have unexpectedly revealed that the strontium ion plays a more significant role in bone and cartilage maintenance than was known before the year 2000. Thus, recent studies suggest that when a water-insoluble strontium salt such as strontium ranelate or strontium succinate is administered orally as a treatment for osteoporosis, the strontium ion (the active ingredient) has an unexpected and unique mechanism of action mediated by a cation-sensing receptor (e.g., the calcium-sensing receptor), the receptor activator of nuclear factor kappa B (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) pathway, and the fibroblast growth factor (FGF)/FGF receptor system. Strontium appears to beneficially increase pre-osteoblast proliferation, osteoblast differentiation, collagen type I synthesis, and bone matrix mineralization while inhibiting osteoclast differentiation and activation. This proposed dual mechanism of action has yielded significant positive effects on bone quality as assessed by diagnostic techniques such as high-resolution peripheral quantitative computed tomography (hr-pQCT) and microCT, as well as x-ray fluorescence (XRF). Both animal and human studies have shown that strontium is almost exclusively found in newly formed bone where it has been incorporated as apatite crystals. Higher levels of strontium are detected in cancellous than in cortical bone. Strontium is also reported to reduce the concentration and/or activity of inflammatory cytokines and mediators.
Of significance, studies of strontium ranelate showed that human exposure to therapeutic doses of the strontium ion does not cause gastric irritation, esophageal cancer, colon cancer, or osteonecrosis of the jaw—side effects which are common to other osteoporosis drug treatments that only slow osteoclast activity and bone resorption (such as bisphosphonates and desunomab).
All of the strontium salts in clinical use today (e.g., strontium ranelate, strontium succinate, strontium citrate, and strontium oxide) are water-insoluble strontium salts having a solubility in water of less than about 5 g/100 mL of water. None can be administered as solutions for injection. After ingestion, all require dissolution by stomach acid to release the strontium ion for uptake in the small intestine.
As a practical matter, however, most subjects using conventional water-insoluble strontium salts for the treatment of bone or joint disorders (such as osteoporosis or osteoarthritis, for example) are adults aged 40 or older who are afflicted with a variety of inflammatory metabolic disorders that adversely affect the gastrointestinal system. One example of the adverse effects of metabolic disorders on the gastrointestinal system is acid reflux. Individuals having acid reflux will consume over-the-counter treatments such as antacids (e.g., Pepcid), esomeprazole (e.g., NEXIUM) or omeprazole (e.g., PRILOSEC) to reduce stomach acidity from about pH 1 to about pH 5 and mitigate the acid reflux and inflammatory bowel disorders that many experience. As a result, water-insoluble treatments like strontium ranelate that require exposure to acidic gastric fluid for strontium release will be less effective. These water-insoluble salts will not dissolve extensively in the near neutral stomach fluids and will not release as much strontium ion as is needed for efficacy.
Thus, there is an unmet need for a water-soluble strontium salt (i.e., one having a solubility in water of greater than about 25 g/100 mL) that will release strontium ion in neutral solutions (e.g., solutions having a pH of 6-8). The present invention provides methods for the preparation and use of pharmaceutical quality strontium L-lactate compositions, a water-soluble strontium salt that meets these criteria and is expected to act both efficaciously and safely when used nutritionally or medicinally.